Collagen is the main component of the connective tissue and it is mostly found in fibrous tissues such as tendon, ligament and skin. Numerous diseases and conditions are associated with excess collagen deposition, the most common are Dupuytren's disease and Peronei's disease.
Dupuytren's disease (DD) is a connective tissue disorder of abnormal collagen production and deposition in the hand that is commonly characterized by contracture of metacarpophalangeal joints (MCPJs) and proximal interphalangeal joints (PIPJs) in the ring and little fingers. Fibroblast proliferation and differentiation into myofibroblasts with excess collagen deposition at the level of the palmar fascia cause nodule and fibrotic cord formation in the palm and/or digits. The fibrotic cords or nodules can be of varying thicknesses, from 1 millimeter in diameter for the fibrotic cords to nearly 10 millimeters in diameter for the fibrotic nodules. As the disease progresses, cords begin to contract, causing finger flexion-deformities (flexion contractures) which interfere and decrease hand function.
The prevalence of DD increases with age and males are more often affected. Genetic susceptibility, smoking, alcohol, diabetes mellitus, epilepsy and repetitive manual work are thought to be common risk factors for DD. The severity and progress of DD can be classified by the affected degree of digital flexion-contracture.
Surgical fasciectomy is currently the most widely available treatment for DD which provides positive, though temporary outcomes for most patients. However, surgical fasciectomy usually involves common surgical complications (e.g., infection, hematoma, tissue loss) as well as specific complications such as digital nerve damage, loss of fingers, skin flap loss, wound healing problems and postoperative stiffness. In addition, fasciectomy involves a long recovery and does not offer a definitive cure as DD has an extremely high recurrence rate. Minimally invasive procedures using needles or thin blades have been tried; such procedures though cause less complications, increase the recurrence rate. Non surgical interventions have also been developed and include radiotherapy, ultrasound, injection of vitamin A, vitamin E, steroids and interferon-γ.
In vitro studies have demonstrated the ability of collagenase to decrease the tensile modulus and the force needed to rupture Dupuytren's cord tissue, indicating that collagenase may be effective in enzymatic fasciotomy. Clinical studies have recently demonstrated that treatment with Clostridium histolyticum collagenase released DD contractures and improved the range of motion in affected joints. An 8-year follow-up of collagenase injection in patients with DD showed that the MCPJ contracture was less severe following the recurrence of the disease, when compared to the initial contracture before applying the collagenase treatment. It has also been shown that Type-III collagen, which is usually absent from normal adult palmar fascia, is abundant in the tissue of patients with DD.
Peyronie's disease is a connective tissue disorder involving the growth of fibrous plaques rich in collagen in the soft tissue of the penis affecting up to 10% of men. Specifically, the fibrous plaques are formed in the tunica albuginea, the thick sheath of tissue surrounding the corpora cavernosa, cause abnormal curvature which is often associated with pain.
Surgery is the only approach to treating Peyronie's disease which appears to have predictably repeatable efficacy. Surgery is usually only indicated in long-term cases where the disease is stabilized and the deformity prevents intercourse and/or causes extreme pain. However, complications can develop from surgery, including a permanent shortening of the penis.
Non-surgical approaches to Peyronie's disease treatment are also available, although they are all largely ineffective. Attempts to dissolve the plaques by direct intra-lesional injections have been tried. Of the injection methodologies, those involving clostridial collagenase appear to exhibit the most consistent efficacy, though still quite limited in effect and duration. In addition, radiation therapy and laser technology have been tried.
U.S. Pat. Nos. 5,589,171, 6,086,872 and Reissued U.S. Pat. No. RE39,941 disclose methods of treating an individual suffering from Dupuytren's disease which methods comprise applying collagenase to a fibrous affected palmar fascia.
U.S. Pat. No. 6,022,539 discloses methods of treating an individual suffering from Peyronie's disease which methods comprise injecting collagenase into a fibrous Peyronie's plaque in the penis of the individual.
U.S. Pat. No. 6,353,028 discloses topical medicament which comprises calcium channel blocker agents and carrier agents facilitating transdermal delivery of the calcium channel blocker for the treatment of connective tissue disorders: Peyronie's disease, Dupuytren's disease and Ledderhose Fibrosis.
U.S. Patent Application Publication No. 2008/0206228 discloses a medicament containing hyaluronic acid or derivatives thereof in association with collagenase for the treatment of various kinds of wounds, burns, pressure sores, vascular ulcers, and diabetic foot ulcers as well as for the treatment of hypertrophic and keloid scars. Treatment of Dupuytren's disease is explicitly disclosed.
International Patent Application Publication No. WO 2004/037183 discloses methods and compositions for treatment of conditions involving fibrosis, among which Peyronie's disease and Dupuytren's disease are disclosed. The compositions comprise a phosphodiesterase (PDE)-4 inhibitor, a PDE-5 inhibitor or a compound that elevates cGMP, to list some.
Use of cell cycle inhibitors, including anti-microtubule agents, antimetabolites, alkylating agents, vinca alkaloids, PDE inhibitors, matrix metalloproteinase including collagenases, for treating a contracture such as Dupuytren's contracture or Peyronie's contracture is disclosed in International Patent Application Publication No. WO 2005/074913.
Nowhere in the background art is it disclosed or suggested that proteolytic enzymes from plant sources are useful for treating connective tissue disorders involving excess collagen deposition.
Extracts derived from the stem of the pineapple plant (Ananas comosus) have been found to selectively remove devitalized tissue. Such extracts, also named bromelain, contain various proteolytic and hydrolytic enzymes.
International Patent Application Publication No. WO 2006/054309 to the applicant of the present invention discloses a debriding composition obtained from bromelain comprising most of the proteolytic enzymes present in bromelain, the proteolytic enzymes having an average molecular weight of 23 kDa. WO 2006/054309 further discloses uses of said debriding composition for debriding non-viable tissues.
There remains an unmet need for improved non-invasive methods for treating connective tissue diseases involving excess collagen deposition.